The invention relates generally to use of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase in treating cancer. More specifically the invention relates to use of lovastatin and its homologues or analogues to treat human adenocarcinoma and selected sarcomas.
Metastatic prostate cancer and stomach cancer are refractory to all available cytotoxic agents. There is no curative medical therapy for these common adult carcinomas. Lovastatin, widely used for treatment of hypercholesterolemia, is generally believed to be useful for synchronizing tumor cell growth in one cell cycle phase. Although there exist scattered reports of the cytotoxic activity of lovastatin, it has not been pursued as an anticancer drug.
Adenocarcinoma is a group in the histological classification of cancer. For instance, 95% of prostate carcinomas are adenocarcinomas. Cancers of the stomach, intestine and colon are almost always adenocarcinomas, as are gall bladder cancers. Breast cancer is also an adenocarcinoma in perhaps 90% of the cases. Cancer of the esophagus is adenocarcinoma in about 10%-15% of cases and adenocarcinoma of the lung represents about 30% of pulmonary cancers.
One of the challenges in treating cancer is the ability to follow the course of the disease and the efficacy of therapy with some objective marker. Ideally, the marker would be obtainable by either noninvasive or minimally invasive means such as a blood test. The marker may be useful in diagnosing a type of cancer as well as in evaluating the prescribed therapy.
An example of a tumor marker is prostate specific antigen (PSA). Serum PSA is clinically useful to monitor the therapeutic response of prostatic cancer patients. See Hudson et al., Clinical Use of Prostate Specific Antigen in Patients With Prostate Cancer, Journal of Urology 142:1011-1017 (October 1989).
Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG Co-A) are known. HMG Co-A catalyzes a crucial step in the biosynthesis of cholesterol. Inhibitors of this enzyme are well known as cholesterol lowering agents. See U.S. Pat. No. 3,983,140 to Endo et al which is incorporated by reference herein. Examples of these inhibitors include the group of physiologic active substances ML-236. Compactin (ML-236B) is a member of this group, and it has been isolated from cultures of Penicillium brevicompatum and Penicillium citrinum. See '140 to Endo et al. See also Brown et al, Crystal and Molecular Structure of Compactin, a New Antifungal Metabolite From Penicillium Brevicompatum, Journal Chemical Society Perkins Trans. I 1165-1170 (1976).
The structures of compactin and some of its homologues are well characterized, and their total synthesis has been achieved by a number of groups. See for example Grieco et al, Total Synthesis of the Hypocholesterolemic Agent Compactin, Journal American Chemical Society 105:1403-1404 (1983), Wang et al, Total Synthesis of Compactin (ML-236B), Journal American Chemical Society 103:6538-6539 (1981), and Hsu et al, Total Synthesis of the Hypocholesterolemic Agent Compactin, Journal American Chemical Society 105:593-601 (1983).
The structural formula of some of the known inhibitors of HMG Co-A is represented by formula I ##STR1## wherein R.sup.1 is a hydrogen atom, a hydroxy group, a 2-methylbutyryloxy group (--OCOCH(CH.sub.3)CH.sub.2 CH.sub.3) or a 2,2-dimethylbutyryloxy group (--OCOC(CH.sub.3) 2CH.sub.2 CH.sub.3) and R.sub.2 is a hydrogen atom or a methyl group. In lovastatin, R.sub.1 is a 2-methylbutyryloxy group and R.sub.2 is a methyl group. In the compound mevastatin, R.sub.1 is a methyl group and R.sub.2 is a hydrogen atom. Simvastatin has a 2,2-dimethylbutyryloxy group in the R.sub.1 position and a methyl group in the R.sub.2 position.
A number of therapeutic measures, such as surgical excision, chemotherapy and radiation, are available in cancer therapy. Frequently, a combination regimen using more than one of the above-mentioned modalities is employed. Additionally, an array of chemotherapeutic agents may be used in treating any one cancer patient. If a tumor marker is available, then knowledge of its abundance may help the clinician tailor the therapeutic regimen. For example, if a patient suffering from prostatic carcinoma receives a drug which lowers his PSA, then the clinician may conclude that the tumor is regressing. Thus, he will alter the patient's therapy accordingly.